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Nat Immunol. 2015 Mar;16(3):276-85. doi: 10.1038/ni.3085. Epub 2015 Jan 19.

The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells.

Author information

1
1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
2
1] Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. [2] Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo, Japan. [3] Division of Immunobiology, Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
3
Laboratory for Mucosal Immunity, RIKEN Research Center for Integrative Medical Sciences, Yokohama, Japan.
4
1] Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo, Japan. [2] Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
5
Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
6
Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
7
1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] The Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.
8
1] The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria, Australia.
9
1] Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. [2] Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.

Abstract

Foxp3(+) regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.

PMID:
25599561
DOI:
10.1038/ni.3085
[Indexed for MEDLINE]

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